DESCRIPTION: There is a significant unmet need for new approaches to diagnose, prevent, and treat post-traumatic headache in Veterans who have suffered traumatic brain injury (TBI). The major aim of this proposal is to use photosensitivity as an objective biomarker of post-traumatic headache for testing two novel treatment strategies. Post-traumatic headache is a debilitating condition that is often characterized by symptoms of chronic migraine. This similarity with chronic migraine provides a timely rationale for testing a new monoclonal antibody that has proven effective in early clinical trials for preventing migraine. Post-traumatic headache is unfortunatel very prevalent in Veterans of the Iraq and Afghanistan conflicts who have experienced a traumatic brain injury (TBI). Post-traumatic headache with concurrent photosensitivity are two of the most prevalent problems reported by military personnel following TBI. This photosensitivity is commonly referred to as photophobia and may occur independently or in association with headache. To date, there is no objective measurement of headache or photophobia. This proposal will test the hypothesis that photosensitivity in mice will be a useful diagnostic tool fo testing of candidate drugs. In the first aim, the plan will be to establish photosensitivity in mic following mild TBI as a preclinical model for post-traumatic headache. An overpressure chamber protocol will be used to model mild blast injury. Photosensitivity will be measured in a transgenic mouse model using a combination of light aversive behavior and translatable assays of periocular responses and facial discomfort. Our preliminary data indicate there is time-dependent development of light aversion in wild type mice following overpressure exposure. Development of these assays will establish an optimal preclinical model for testing candidate drugs to treat or prevent post-TBI headache. In the second aim, we will evaluate the therapeutic efficacies of two complementary agents: (1) a monoclonal antibody against the neuropeptide calcitonin gene-related peptide (CGRP), and (2) a neuroprotective agent (P7C3-S243) that our team has recently shown to reduce blast- induced neural damage. The effects of a CGRP-blocking antibody and P7C3-S243 will be tested by monitoring light aversion and the periocular and facial responses post-TBI. Histochemical markers of axonal degeneration and cell death in regions implicated in photosensitivity will also be examined as indicators of efficacy after P7C3-S243 treatment. A strength of this study is that we have formed an interdisciplinary multi-PI team with expertise in molecular and behavioral neurosciences, biomedical engineering, and clinical aspects of photophobia, who are all members of the VA Center for the Prevention and Treatment of Vision Loss. The significance of this study is the potential clinical application of to classes of promising therapeutic agents to improve the quality of life in a large population of Veterans. The expected results will establish an objective measurement of an otherwise subjective pain state that affects a disproportionately large number of Veterans with post-traumatic headache. Importantly, this study will provide the foundation for future clinical trials using the CGRP antibody and P7C3 agents for treatment of Veterans who have suffered from mild TBI.